National Medical Policy - Health Net Cell Tandem Transplants Jun 17 1 National Medical Policy...

Stem Cell Tandem Transplants Jun 17 1

National Medical Policy Subject: Tandem Stem Cell Transplants in the Adult Patient

Policy Number: NMP331

Effective Date*: March 2007

Update: June 2017

This National Medical Policy is subject to the terms in the

IMPORTANT NOTICE

at the end of this document

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Use Source Reference/Website Link

X National Coverage Determination

(NCD) Stem Cell Transplantation:

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database/search/advanced-search.aspx

National Coverage Manual Citation

Local Coverage Determination (LCD)*

Article (Local)*

Other

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Current Policy Statement Planned tandem transplantations (also known as sequential or double transplants)

consisting of an initial regimen of high dose chemotherapy (HDC) with autologous

stem cell support followed by another course of HDC with autologous transplant or

an allogeneic transplant using a suitably matched HLA donor of a close family

relative (e.g., preferably sibling) usually within a period of 2 to 6 months of each

other is considered medically necessary for any of the following malignancies in

patients with low to moderate surgical risk and no significant comorbid medical

conditions*:

1. Patients with primary testicular cancer who are in the first or second relapse or

whose tumors are refractory to a cisplatin-based chemotherapeutic regimen

2. For patients with multiple myeloma when all of the following are met:

Patient has Durie-Salmon stage I (one bone lesion), Stage II or III

myeloma (see table on Stages of Multiple Myeloma in Scientific Rationale

section); and

Patient has newly diagnosed or chemoresponsive multiple myeloma.

3. As an option for patients with multiple myeloma who do not achieve at least a very

good partial response (VGPR*) after the first autologous SCT. This should preferably

be done within a clinical trial.

*Note: VGPR refers to serum and urine M-protein detectable by immunofixation but

not on electrophoresis, or 90% or greater reduction in serum M-protein plus urine M-

protein level <100 mg per 24 hours. [i.e., Monoclonal (M)-proteins are found in both

the serum and/or urine of patients with a wide variety of clinical conditions. Serum

protein electrophoresis (SPEP) detects the presence and level of various proteins in

the blood, including M protein. Serum protein electrophoresis is used to identify

patients with multiple myeloma and other serum protein disorders. Urine Protein

Electrophoresis (uPEP) can provide quantification of the M protein. In monoclonal

gammopathies, a proteinuria pattern may show a discrete band produced by

monoclonal free light chains, or Bence-Jones Proteinuria (BJP)].

Note: Health Net, Inc. considers planned tandem transplantation not medically

necessary, in patients with indolent myeloma, smoldering myeloma, and monoclonal

gammopathy of uncertain significance [MGUS] because there is insufficient scientific

evidence in the medical literature as to its safety and effectiveness.

* General Criteria for Patient Selection – patient must have all of the

following:

Be medically compliant and free of an active substance or alcohol abuse problem; and

Be free of any active comorbid disease which would significantly reduce

short- term life expectancy


Specifically, Health Net, Inc. consider all of the following indications for tandem stem

cell transplant investigational, because although trials are ongoing, there is

insufficient scientific evidence in the medical literature to validate their safety and

effectiveness.

An initial course of high dose chemotherapy with autologous stem cell

transplantation (AuSCT) followed by non-marrow ablative chemotherapy

with AuSCT (“mini-transplant”) to treat multiple myeloma

Treatment of patients with amyloidosis

Treatment of patients with any stage, grade, or sub-type of Non-Hodgkin’s

Lymphoma (NHL)

Treatment of solid tumors of childhood

Health Net, Inc. considers all of the following indications for tandem stem cell transplant not

medically necessary:

Performance of the second course of chemotherapy and stem-cell support

at an interval of > 6 months after the first course

Planned tandem autologous stem cell transplantation as a treatment of all

other non-testicular germ cell tumors

A second or repeat allogeneic (ablative or non-myeloablative) transplant

due to persistent, progressive or relapsed disease

Treatment of PNETs including medulloblastoma and ependymoma

Treatment of Waldenstrom’s Macroglobulinemia

Codes Related To This Policy The codes listed in this policy are for reference purposes only. Listing of a code in this policy

does not imply that the service described by this code is a covered or non-covered health

service. Coverage is determined by the benefit documents and medical necessity criteria.

This list of codes may not be all inclusive.

On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and

inpatient procedures have been replaced by ICD-10 code sets.

ICD-9 Codes 203.00-203.01 Multiple myelomas

164.2-164.9 Malignant neoplasm of mediastinum

186.0-186.9 Malignant neoplasm of testis

ICD-10 Codes C38-C38.8 Malignant neoplasm of heart, mediastinum and pleura

C62-C62.92 Malignant neoplasm of testis

C90-C90.32 Multiple myeloma and malignant plasma cell neoplasms

CPT Codes 38204 Management of recipient hematopoietic progenitor cell donor

search and cell acquisition


38205 Blood-derived hematopoietic progenitor cell harvesting for

transplantation, per collection; allogeneic

38206 Blood-derived hematopoietic progenitor cell harvesting for

transplantation, per collection; autologous

38207-38215 Transplant preparation of hematopoietic progenitor cells

38230 Bone marrow harvesting for transplantation, allogeneic

38232 Bone marrow harvesting for transplantation, autologous

38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation

per donor

38241 Hematopoietic progenitor cell (HPC); autologous transplantation

HCPCS Codes S2142 Cord blood-derived stem cell transplantation, allogeneic

S2150 Bone marrow or blood-derived peripheral stem cells (peripheral or

umbilical), allogeneic or autologous, harvesting, transplantation,

and related complications; including pheresis and cell

preparation/storage, marrow ablative therapy, drugs, supplies,

hospitalization with outpatient follow-up, medical/surgical,

diagnostic, emergency, and rehabilitative services, and the

number of days of pre- and post-transplant care in the global

definition

Scientific Rationale – Update May 2016 The NCCN Guidelines (Version 3.2016) on Multiple Myeloma notes that “Potential

transplant candidates must undergo a stem cell harvest, collecting enough stem cells

for two transplants in anticipation of a tandem transplant or a second transplant,

within 6 months, as subsequent therapy. Alternatively, all patients may consider

continuation of primary therapy until the best response is reached. The optimal

duration of primary therapy after achieving maximal response is unknown; hence

maintenance therapy or observation can be considered beyond maximal response”.

The NCCN Guidelines (Version 2.2016) on Testicular Cancer notes: “Patients who do

not experience a durable complete response to first-line therapy or those who

experience a recurrence can be divided into those with a favorable or unfavorable

prognosis based on prognostic factors. These factors can be used in deciding whether

a patient is a candidate for conventional dose therapy or high-dose therapy with

stem cell support as a second line option”. Scientific Rationale – Update May 2015 Byrne et al (2015) reported on a prospective phase II clinical trial of multiple

myeloma (MM) patients who were randomized to receive a second (tandem)

autologous stem cell transplantation (ASCT) based on whether they achieved a

partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who

achieved a very good partial response or better (≥VGPR) had salvage ASCT at

relapse. Seventy-five patients received conditioning therapy and ASCT1. A total of 44

patients (59%) achieved ≥VGPR, whereas 31 patients entered ≤PR and were offered

tandem ASCT. In all, 20 patients agreed to tandem ASCT. Demographic and clinical

characteristics were similar between the two cohorts except for median lactate

dehydrogenase (LDH) (P= 0.0141) and percentage of marrow plasma cells before

ASCT1 (P = 0.0047), both lower in the ≥VGPR group. Intent to treat analysis showed

that patients who achieved ≥VGPR to ASCT1 had a trend toward improved

progression-free survival (PFS) (37 vs. 26 months, P = 0.078) and superior overall


survival (OS) (not reached vs. 50 months, P = 0.0073). Patients with ≤PR who

declined tandem transplantation had shortened PFS (20 vs. 28 months, P = 0.05)

but similar OS (53 vs. 57.5 months, P = 0.29) compared to those who received it.

Thus, a favorable clinical response to ASCT1 identifies a low-risk group with superior

long-term prognosis despite similar PFS.

Iacobelli et al (2015) reported that previous studies have shown that obtaining

complete hematologic remission (CR) in multiple myeloma is an important predictor

of PFS and OS. This applies both to autologous and allogeneic transplantation.

However, the importance of CR obtained before vs after second transplant or

following allogeneic vs autologous transplantation is not clear. The author

investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional

prospective study comparing tandem autologous/reduced intensity conditioning

allogeneic transplantation (auto/RICallo) to autologous transplantation-single or

double (auto/auto). Allocation to treatment was performed according to availability

of a matched sibling donor. Cox regression and multi-state models were applied. The

long-term probability of survival in CR was superior in auto/RICallo, both comparing

groups according to treatment allocated at start (28.8 vs 11.4% at 60 months,

P=0.0004) and according to actual administration of second transplant (25.6 vs

9.6% at 60 months, P=0.008). CR achieved before the second transplant was

predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047)

irrespective of the type of second transplant. CR achieved after auto/RICallo was

more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81,

P=0.390), indicating a better durability of CR obtained after an allotransplant

procedure.

Scientific Rationale – Update May 2014 High-dose therapy with stem cell support is a critical component in the treatment

plan for eligible patients with newly diagnosed multiple myeloma (MM.) The types of

stem cell transplant (SCT) may be single autologous SCT, a tandem SCT (a planned

second course of high-dose therapy and SCT within 6 months of the first), or an

allogeneic SCT. An allogeneic SCT can either be performed after prior myeloablative

therapy or after nonmyeloablative therapy. A tandem transplant differs from a repeat

transplantation which is requested or performed more than 6 months after the first

transplant, and is used as salvage therapy after failure of initial transplantation or

relapsed disease. Nonmyeloablative therapy, also referred to as “mini transplant,”

is a technique to decrease toxicity of the allotransplant while preserving the

alloimmune graft-versus-myeloma effect. An allogeneic SCT may also follow an

autologous SCT.

Autologous SCT results in high response rates and remains the standard of care after

primary therapy for eligible patients with multiple myeloma. The NCCN Multiple

Myeloma panel recommends collecting enough stem cells for two eligible transplants

in ALL eligible patients. Per the Multiple myeloma panel, a tandem transplant with or

without maintenance therapy can be considered for all patients who are candidates

for SCT and is an option for patients who do not achieve at least a very good

partial response (VGPR) after the first autologous SCT. The benefit from the second

transplant in patients who are in complete response (CR), or VGPR and also in those

who achieve less than VGPR after the first SCT should preferably be answered in a

clinical trial. The other option for this group of patients includes maintenance

therapy or observation. NCCN notes that a randomized prospective NIH and

intergroup-supported trial is currently ongoing.


Imrie et al (2009) published guidelines on stem cell transplantation

recommendations in adults. Per the guidelines:

Autologous stem cell transplantation is the recommended treatment option for

eligible younger patients (under age 65-70 years) with newly diagnosed MM.

Tandem (double) autologous stem cell transplantation is an option for patients

who obtain less than a complete response to the first autologous transplant.

Repeat autologous transplantation is an option for patients with MM who relapse

after a long remission (> 2 years) to a single autologous transplant.

Allogeneic transplantation is an option for selected patients with MM including

those with high-risk cytogenetics and those whose disease is unresponsive to

primary therapy.

The guidelines states further that the evidence on the role of stem cell

transplantation in the management of multiple myeloma is rapidly emerging.

Kozelj et al (2013) reported that tandem autologous hematopoietic stem cell

transplantation (ta-HSCT) is a standard treatment for multiple myeloma (MM).

Patients receive a high-dose cyclophosphamide (CY), followed by two myeloablative

cycles of melphalan (MEL). There are scarce data about long term cardiotoxicity.

The authors studied 12 patients (62.25 ± 8.55 years) six years after the completion

of MM treatment with ta-HCST. Late cardiotoxic effects were evaluated clinically and

echocardiographically. None of the patients developed clinical signs of heart failure,

all were in sinus rhythm and NT-pro BNP concentration was elevated (778 ± 902.76

pg/mL). The left ventricular (LV) size remained normal. The LV ejection fraction did

not decrease (73.75 ± 5.67%, 69.27 ± 6.13%, p = NS). The LV diastolic function

parameters (E, A, ratio E/A and A/a) did not change significantly. In tissue Doppler

parameters we observed a nonsignificant decrease in Em (10.26 ± 2.63 cm/s, 7.57

± 1.43 cm/s) and Sm velocities (8.7 ± 0.87 cm/s, 7.14 ± 1.17 cm/s, p = NS). The

E/Em values were in an abnormal range (8.66 ± 1.05, 10.55 ± 2.03). The authors

concluded the treatment of MM with ta-HSCT, during which patients receive a high

dose CY followed by two myeloablative cycles of MEL, causes mild, chronic, partially

reversible and clinically silent cardiotoxic side-effects. However, ta-HSCT in patients

with MM is a safe regarding cardiotoxic side effects, but, because of increasing life

expectancy needs long term attention.

Gahrton et al (2013) reported long-term follow-up of prospective studies comparing

allogeneic transplantation to autologous transplantation in multiple myeloma is few and

controversial. They reported an update at a median follow-up of 96 months of the European

Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell

transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem

autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to

autologous transplantation alone (auto). There are 357 myeloma patients up to age 69

years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n =

108) and those without to auto alone (n = 249). At 96 months progression-free survival

(PFS) and overall survival (OS) were 22% and 49% vs 12% (P = .027) and 36% (P = .030)

with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL)

was 60% vs 82% (P = .0002). Non-relapse mortality at 36 months was 13% vs 3% (P =

.0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and

47% vs 5% (P = .026), and 31% (P = .154). Long-term outcome in patients with multiple

myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo

approach seemed to overcome the poor prognostic impact of del(13) observed after


autologous transplantation. Follow up longer than 5 years is necessary for correct

interpretation of the value of auto/RICallo in multiple myeloma.

Kharfan-Dabaja et al (2013) reported that despite advances in understanding of

clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of

more effective therapies, MM remains incurable. The autologous-allogeneic (auto-

allo) hematopoietic cell transplantation (HCT) strategy is based on combining

cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive

immunotherapy. However, conflicting results have been reported when an auto-allo

HCT approach is compared to tandem autologous (auto-auto) HCT. The authors

performed a systematic search that identified 152 publications, of which five studies

(enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion

utilized biologic randomization. Assessing response rates by achievement of at least

a very good partial response did not differ among the treatment arms [risk ratio (RR)

(95% CI)=0.97 (0.87-1.09), p=0.66]; but complete remission was higher in the

auto-allo HCT arm [RR=1.65 (1.25-2.19), p=0.0005]. Event-free survival did not

differ between auto-allo HCT group versus auto-auto HCT group using per-protocol

analysis [hazard ratio (HR)=0.78 (0.58-1.05)), p=0.11] or using intention-to-treat

analysis [HR=0.83 (0.60-1.15), p=0.26]. Overall survival (OS) did not differ among

these treatment arms whether analyzed on per-protocol [HR=0.88 (0.33-2.35),

p=0.79], or by intention-to-treat [HR=0.80 (0.48-1.32), p=0.39] analysis. Non-

relapse mortality (NRM) was significantly worse with auto-allo HCT [RR

(95%CI)=3.55 (2.17-5.80), p<0.00001]. The reviewers concluded despite higher

complete remission rates, there is no improvement in OS with auto-allo HCT; but this

approach results in higher NRM in patients with newly diagnosed MM. At present,

totality of evidence suggests that an auto-allo HCT approach for patients with newly

diagnosed myeloma should not be offered outside the setting of a clinical trial.

Armeson et al (2013) utilized meta-analysis to compare tandem autologous (TA)

hematopoietic SCT (auto-HSCT) or single auto-HSCT followed by reduced intensity

conditioning (RIC), allogeneic (AR) hematopoietic SCT in the upfront management of

patients with multiple myeloma (MM). A comprehensive search strategy of published and

unpublished reports utilized the following entry criteria: newly diagnosed patients, first

autologous transplantation in both arms, use of an RIC regimen and assignment to TA or AR

based exclusively on the availability of an HLA matched donor. Six trials were identified

yielding 1192 subjects in TA and 630 in AR. Patients in AR had higher likelihoods of TRM

(relative risk (RR)=3.3, 95% confidence interval (CI)=2.2-4.8) and CR (RR=1.4, 95%

CI=1.1-1.8). OS was not different in the first 36 months (hazard ratio (HR)=1.15, 95%

CI=0.91-1.45) or after (HR=0.74, 95% CI=0.53-1.04) 36 months from assignment. Similar

findings were seen for PFS. When compared with TA in the upfront management of MM, AR

is associated with higher TRM and CR without improvement in PFS or OS.

At this time, there is a clinical trial, a multicenter, prospective phase II-study investigating

safety and efficacy of the combination of auto-allo tandem stem cell transplantation in

patients with multiple myeloma and age of >55 years, followed by maintenance therapy

with low-dose Thalidomide and Donor Lymphocyte Infusions currently recruiting participants

(NCT00777998). Numerous other trials were identified on the Clinical trial.gov website

investigating tandem SCT for a variety of indications (e.g., high-risk neuroblastoma,

relapsed or refractory lymphoma, high risk solid tumors, refractory acute leukemia)

Scientific Rationale – Update May 2013 The NCCN Multiple Myeloma Panel (2013) recommends:


Collecting enough stem cells for two transplants, in all eligible patients. They state:

“A tandem transplant can be considered for all multiple myeloma patients who are

candidates for stem cell transplant (SCT), and is an option for patients who do not

achieve at least a very good partial response (VGPR) after the first autologous SCT.

The benefit from the second transplant in patients who are in complete response

(CR), or VGPR and also in those who achieve less than VGPR after the first SCT

should preferably be answered in a clinical trial.” The other option for this group of

patients includes maintenance therapy or observation.

The International Myeloma Working Group has response criteria for multiple

myeloma disease progression and relapse. Progressive disease is to be used for

calculation of time to progression and progression-free survival and points for all

patients including those in complete remission. Progressive disease requires one or

more of the following and an increase of > 25% from baseline in:

Serum M-component and/or (the absolute increase must be > 0.5g/Dl)2

Urine M-component and/or (the absolute increase must be > 200mg/24 hours

Only in patients without measurable serum and urine M-protein levels: the

difference between involved and uninvolved free light chain (FLC) levels. The

absolute increase must be over 10 mg/Dl

Bone marrow plasma cell percentage: the absolute % must be > 10%3

Definitive development of new bone lesions or soft tissue plasmacytomas or

definite increase in the size of existing bone lesions or soft tissue

plasmacyutomas

Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or

2.65 mmo/L) that can be attributed solely to the plasma cell proliferative

disorder

Monoclonal or M-proteins are found in both the serum and/or urine of patients with a wide

variety of clinical conditions. The occurrence and clinical symptoms of these conditions vary

widely. Clearly the significance of M-proteins varies widely and the mere presence of an M-

protein must be evaluated in the clinical context for each patient.

Serum protein electrophoresis (SPEP) detects the presence and level of various proteins in

the blood, including M protein. Serum protein electrophoresis is used to identify patients

with multiple myeloma and other serum protein disorders. Electrophoresis separates

proteins based on their physical properties, and the subsets of these proteins are used in

interpreting the results. A homogeneous spike-like peak in a focal region of the gamma-

globulin zone indicates a monoclonal gammopathy. Monoclonal gammopathies are

associated with a clonal process that is malignant or potentially malignant, including

multiple myeloma, Waldenström’s macroglobulinemia, solitary plasmacytoma, smoldering

multiple myeloma, monoclonal gammopathy of undetermined significance, plasma cell

leukemia, heavy chain disease, and amyloidosis. The quantity of M protein, the results of

bone marrow biopsy, and other characteristics can help differentiate multiple myeloma from

the other causes of monoclonal gammopathy.

For the urine, it is important to follow the monoclonal free light chains and not the intact M-

protein immunoglobulin that may be found in the urine. The prognosis and threat to the

kidney is mainly due to the amount of monoclonal free light chain and not due to the intact

M-protein. Urine Protein Electrophoresis (uPEP) can provide quantification of the M protein.

In monoclonal gammopathies, a proteinuria pattern may show a discrete band produced by

monoclonal free light chains, or Bence-Jones Proteinuria (BJP).


The 2013 NCCN guidelines on Multiple Myeloma include and note this clinical trial by Fenk et

al. (2011), a retrospective case –matched control analysis, that was done comparing

patients who underwent a 2nd autologous SCT to those treated with conventional

chemotherapy for relapsed multiple myeloma. Similar to previously published smaller

studies, this analysis demonstrated that a 2nd autologous SCT is associated with superior

relapse-associated mortality compared with conventional chemotherapy (68% versus 78%)

along with improved overall survival (OS) (32% versus 22%) at 4 years. In this analysis,

factors associated with improved OS and progression free survival (PFS) included younger

age (<55 years), beta-2 microglobulin <2.5 mg/L at diagnosis, a remission duration of >9

months and a greater than partial remission (PR) to their 1st autologous SCT. This analysis

indicates that a 2nd autologous SCT, for relapsed or progressive MM patients, may be an

option for carefully selected patients. Some of these patients can achieve durable complete

or partial remission. Tandem SCT refers to a planned second course of high dose therapy

and SCT within 6 months of the first.

Scientific Rationale – Update March 2013 There is no conclusive evidence that high-dose therapy with or without

hematopoietic stem cell infusion at any point during treatment is beneficial for

patients with poor-risk localized and metastatic Ewing sarcoma family of tumors

(EFT). Seventy per cent of patients with EFT are under the age of 20 years old. Most

patients with advanced or recurrent disease need new approaches to improve

outcomes, and participation in clinical trials should be encouraged. Long-term follow-

up is needed following therapy because disease relapse, treatment-related

complications, and second malignancies all occur beyond five years after treatment

is initiated.

High dose chemotherapy and autologous hematopoietic cell transplantation can

achieve sustained remissions in some patients with recurrent or refractory Hodgkin

lymphoma. However, in the absence of randomized trials, a number of important

issues remain unresolved concerning this approach including patient selection,

choice of procedure, cytoreductive therapy, and the use of adjunctive radiotherapy.

In view of the five percent early mortality and the appreciable risk of late

myelodysplastic syndrome and/or acute myeloid leukemia associated with high dose

chemotherapy and transplantation, this approach should be considered as a

treatment of choice only in patients with a poor prognosis.

When multiple myeloma is suspected, the diagnosis must be carefully verified. For

example, patients who have 10 percent or more clonal plasma cells in the marrow

but no evidence of end organ damage that can be attributed to the plasma cell

disorder (smoldering multiple myeloma) do not require therapy because there is no

proof of clear benefit with currently available therapies, and some of these patients

remain stable without treatment over extended periods of time. (Per Rajkumar

(2013, UpToDate). AL amyloidosis can occur alone or in association with multiple

myeloma or, much less often, Waldenström’s macroglobulinemia or non-Hodgkin

lymphoma.

Per Kieran (2013, UpToDate) the initial treatment for patients with ependymoma

arising in the brain consists of maximal safe resection, which is usually followed by

adjuvant radiotherapy. Chemotherapy does not appear to play an important role in

the management of these tumors in adults and older children, but may in young

children or in patients with bulk residual disease. Until better molecular prognostic

markers are available, current therapeutic approaches continue to focus on the

degree of resection as the major determinant of treatment. Incompletely resected

ependymomas of either grade (II or III) require a short course of chemotherapy


followed by second-look surgery if there is residual signal, followed by conformal

radiation therapy. Ependymomas of either grade that achieve a complete resection

up-front should go directly to conformal radiation therapy. An exception to these

approaches should only occur in the context of approved prospective clinical trials.

Scientific Rationale – Update March 2012 Krishnan et al (2011) aimed to assess effectiveness of allogeneic HSCT with non-

myeloablative conditioning after autologous HSCT compared with tandem autologous

HSCT. In this phase 3 biological assignment trial, investigators enrolled patients

with multiple myeloma attending 37 transplant centers in the USA. Patients (<70

years old) with adequate organ function who had completed at least three cycles of

systemic antimyeloma therapy within the past 10 months were eligible for inclusion.

Investigators assigned patients to receive an autologous HSCT followed by an

allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group)

on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-

auto group subsequently underwent a random allocation (1:1) to maintenance

therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias,

investigators classified patients as standard risk or high risk on the basis of

cytogenetics and β2-microglobulin concentrations. They used the Kaplan-Meier

method to estimate differences in 3-year progression-free survival (PFS; primary

endpoint) between patients with standard-risk disease in the auto-allo group and the

best results from the auto-auto group (maintenance, observation, or pooled). This

study is registered with ClinicalTrials.gov, number NCT00075829. Between Dec 17,

2003, and March 30, 2007, they enrolled 710 patients, of whom 625 had standard-

risk disease and received an autologous HSCT. 156 (83%) of 189 patients with

standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto

group received a second transplant. 219 patients in the auto-auto group were

randomly assigned to observation and 217 to receive maintenance treatment, of

whom 168 (77%) completed this treatment. PFS and overall survival did not differ

between maintenance and observation groups and pooled data were used. Kaplan-

Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and

46% (42-51) in the auto-auto group (p=0·671); overall survival also did not differ at

3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0·191). Within 3 years, 87 (46%)

of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185

(42%) of 436 patients in the auto-auto group. The adverse events that differed most

between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group

vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-

allo group vs 52 [12%] in the auto-auto group). Investigators concluded non-

myeloablative allogeneic HSCT after autologous HSCT is not more effective than

tandem autologous HSCT for patients with standard-risk multiple myeloma. Further

enhancement of the graft versus myeloma effect and reduction in transplant-related

mortality are needed to improve the allogeneic HSCT approach.

Bashir et al (2011) investigated 149 patients with multiple myeloma (MM) who

received allogeneic hematopoietic stem cell transplantation (allo-HCT) with

myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110)

regimens at a single center. Of the total, 120 (81%) patients had relapsed or had

refractory disease. Median age of MM patients was 50 (28-70) years with a followup

time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality

(TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC

regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative

incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and

chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In


multivariate analysis, allo-HCT for primary remission consolidation was associated

with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-

0.55), while absence of high-risk cytogenetics was associated with longer PFS only

(HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of

RIC regimens, and long-term disease control can be expected in a subset of MM

patients undergoing allo-HCT. The investigators recommended further studies should

be conducted in carefully designed clinical trials in this patient population.

Khalafallah et al (2011) investigated the health-related quality of life (HR-QoL) in

patients with multiple myeloma (MM) undergoing tandem autologous stem cell

transplantation (TASCT). Eighteen patients with advanced MM who underwent dose-

modified TASCT were enrolled in this study between March 2006 and March 2008.

Patients <60 year old (10) received conditioning with melphalan 140 mg/m(2) and

patients who were ≥60 years (8) received 100 mg/m(2). The median age was 57.5

years (range 35-69). The investigators conducted the European Organization of

Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-MY24

questionnaires via interviews at presentation, after each ASCT and thereafter every

3 months for 24 months. Mean global health measure improved from 3.44 before

transplant to 4.50 (1=very poor, 7=excellent) at the second and subsequent follow-

up visits (P<0.001) and the mean global quality of life score improved from 3.61 to

4.71 (P<0.001). Pain symptoms were reduced (P=0.001), and physical functioning

improved (P<0.001) throughout the period of post-transplant follow-up. The

investigators concluded the study showed that dose-reduced TASCT is well tolerated

with low toxicity albeit the transient reduction in QoL during both transplants. Post-

transplant follow-up showed significant improvement in overall HR-QoL that reflects

positively on the overall disease-outcome. They noted a sole focus on patient-

survival does not adequately provide indication regarding the tolerability and

effectiveness of a proposed treatment on the patient's perceived quality of life and

the primary concern should be toward patient-welfare as well as survival.

Scientific Rational Update – December 2010 (2011) The National Cancer Comprehensive Network (NCCN) Myeloma Panel recommends

collecting enough stem cells for two transplants in all eligible patients. According to the

NCCN Multiple Myeloma Panel, a tandem transplant can be considered for all patients who

are candidates for stem cell transplant (SCT) and is an option for patients who do not

achieve at least a very good partial response (VGPR) after the first autologous SCT. The

benefit from the second transplant in patients who are in complete remission or VGPR and

also those who achieve less than VGPR after the first SCT, should be answered in a clinical

trial. A randomized perspective NIH and intergroup supported trial is currently ongoing. The

other option for this group of patients includes maintenance therapy or observation.

Planned tandem stem cell transplants (SCT) refer to a planned second course of high dose

therapy and SCT within 6 months of the first. Planned tandem stem cell transplants have

been studied in several randomized control trials. The IFM94 trial reported by Attal et al.

randomized newly diagnosed myeloma patients to single or tandem autologous transplants.

A total of 78% of patients assigned to the tandem transplant group received the 2nd

transplant at a median time of 2.5 months after the first. A variety of options for salvage

therapy were provided. For example, relapsing patients in either group received no

therapy, additional conventional therapy or another stem cell transplant. The probability of

surviving event free was 10% in the single transplant group, compared to 20% in the

double transplant group. The authors of the IFM94 trial have suggested that the

improvement in projected survival associated with tandem transplant is related not to

improved response rates but to longer durations of response.


Four other trials have compared single versus tandem transplant, but none have shown a

significant improvement in overall survival. However, since the median follow-up is 45-53

months, the lack of significant improvement is not surprising. The Cavo Trial found that

patients not in complete remission or near complete remission after the first transplant

benefited the most from a second transplant. This confirms the observations of the IFM94

trial using non-TBI based high dose regimens.

A review of long-term outcomes of several trials of autologous transplantation by Barlogie et

al. (2010) found that tandem transplantations were superior to both single transplants and

standard therapies. Also, post relapse survival was longer when event-free survival was

sustained for at least 3.5 years after tandem transplantation.

The 2010 NCCN guidelines for the treatment of testicular cancer state that if a patient with

favorable prognostic factors (defined as testicular primary site, prior complete response to

first line therapy, low levels of serum markers and low volume disease), experiences an

incomplete response to conventional-dose salvage chemotherapy therapy or relapses after

salvage chemotherapy, high-dose chemotherapy with autologous stem cell support is the

preferred option. Patients with unfavorable prognostic factors for conventional-dose salvage

therapy (e.g. an incomplete response to first line therapy) and patients requiring third-line

salvage therapy are considered for treatment with high-dose chemotherapy plus autologous

stem cell support (category 2B). The 2010 guidelines do not address the use of tandem or

sequential hematopoietic stem cell transplantation (HSCT) in the treatment of testicular

tumors.

Testicular cancer is a unique malignancy in its curability. Long-term followup of patients

treated with chemotherapy suggests that the long-term relapse-free survival for complete

responders is in the range of 80% to 90%. Nonetheless, once a complete remission is

obtained, patients remain at risk for two types of adverse late consequences: relapse,

including contralateral primary testicular neoplasms, and toxicity from therapy.

After obtaining complete remission, 8% to 15% of germ cell tumor (GCT) patients will

relapse, usually within the first 2 years after treatment. The timing of a relapse does not

seem to be dependent on histology, extent of disease, or induction regimen used. Late

recurrences, defined as relapses occurring more than 24 months after diagnosis, have been

reported in 1.5% to 4% of patients achieving a complete response. The majority of late

relapses occur longer than 5 years from diagnosis. Nearly 50% of relapses were

retroperitoneal and 35% intrathoracic (including the mediastinum). Proposed mechanisms

for late relapses include the development of second primary lesions, growth of an occult

contralateral testicle tumor that is not affected by chemotherapy because of the blood-

testicular barrier, the “reactivation” of quiescent carcinoma, or malignant degeneration of

mature teratoma. The latter argument is the most favored, in that teratomatous elements

are observed in either the orchiectomy or relapse specimens in most patients. Teratomatous

elements were present in the orchiectomy specimens of 66% of 21 nonseminomatous germ

cell transplant (NSGCT) patients with a late relapse reported in three series. Nonetheless,

this theory does not account for the 33% of late-relapse NSGCT patients who did not have

teratoma described in their orchiectomy specimen (perhaps a microscopic focus was

missed), or the seven pure seminoma patients in these series who experienced a late

relapse.

A late relapse should be treated aggressively as a de novo malignancy. Outcomes in this

setting are a reflection of the underlying histology at the time of relapse. Patients with

teratoma who are treated surgically have excellent long-term outcomes, whereas the


complete-response rates to chemotherapy alone for those who relapse with viable GCT are

approximately 50%, and the median survival in this setting is approximately 24 months

according to one recent series. Approximately 70% of seminoma patients can be rendered

free of disease with chemotherapy, radiation, or both. Whereas 80% of patients with NSGCT

can currently be cured with platinum-based therapy, 20% will ultimately die of their disease

because of either failure to achieve a complete response with induction therapy or relapse

after becoming disease-free with primary therapy. Before the initiation of salvage therapy,

the diagnosis of relapsed or primarily refractory GCT must be clearly established.

Scientific Rationale Initial Despite treatment with high-dose chemotherapy followed by stem cell transplant,

many patients with advanced malignancies eventually relapse, indicating the

presence of residual neoplastic cells. Tandem high-dose or non-myeloablative

chemotherapy with autologous and/or allogeneic stem cell support is the planned

administration of more than one cycle of high-dose chemotherapy, alone or with

total body irradiation, each of which is followed by re-infusion of stem cells. In the

former the patient is given his own stem cells in an autologous transplantation, and

in the later the patient is given stem cells donated from a matched sibling as an

allogeneic stem cell rescue after a recuperation period of about two to 6 months. The

hypothesis is that eradication of residual tumor cells can be achieved using multiple

cycles of myeloablative or non-myeloablative chemotherapy with stem cell support.

Sibling allogeneic transplants have several potential advantages relative to

autologous transplants, including no chance that the transplant will reinfuse

malignant cells and the possibility that donor cells may mediate immunologic

antitumor effects. The tandem transplant achieves remission rates similar to those

with a high-dose allogeneic transplant but with much lower morbidity and mortality.

Testicular Cancer

Testicular cancer forms in tissues of the testis that make sperm and male hormones

and usually occurs in young- or middle-aged men. Two main types of testicular

cancer are seminomas (cancers that grow slowly and are more sensitive to radiation

therapy) and nonseminomatous germ cell tumors (NSGCTs) (different cell types that

grow more quickly than seminomas). Although the exact cause of testicular cancer is

unknown, several factors seem to increase risk. These include a past medical history

of undescended testicle(s), abnormal testicular development, Klinefelter's syndrome

(a sex chromosome disorder that may be characterized by low levels of male

hormones, sterility, development of breasts, and small testes), or previous testicular

cancer. Between 6,000 and 8,000 men are diagnosed with testicular cancers each

year. Although testicular cancer accounts for 1% of all cancers in men, it is the most

common form of cancer in young men 15 to 40 years old. It may also occur in young

boys, but only about 3% of all testicular cancer is found in this group. Seminomas

account for about 30-40% of all testicular tumors. These are usually is found in men

in their 30s and 40s. The condition is usually localized to the testes, although in

about 25% of cases it has spread to lymph nodes. Non-seminomas account for 60%

of all testicular tumors.

Testicular cancer is a highly treatable, often curable, cancer that usually develops in

young and middle-aged men. For patients with seminoma (all stages combined), the

cure rate exceeds 90%. For patients with low-stage disease, the cure rate

approaches 100%. Tumors that have a mixture of seminoma and nonseminoma

components should be managed as nonseminomas. Nonseminomas include

embryonal carcinomas, teratomas, yolk sac carcinomas and choriocarcinomas, and


various combinations of these cell types. Risk of metastases is lowest for teratoma

and highest for choriocarcinoma, with the other cell types being intermediate.

Tumors that appear to have a seminoma histology but that have elevated serum

levels of alpha fetoprotein (AFP) should be treated as nonseminomas. Elevation of

the beta subunit of human chorionic gonadotropin (hCG) alone is found in

approximately 10% of the patients with pure seminoma.

A number of prognostic classification schema are in use for metastatic nonsemino-

matous testicular cancer and for primary extragonadal nonseminomatous germ cell

cancers treated with chemotherapy. Most incorporate some or all of the following

factors, which may independently predict worse prognosis:

Presence of liver, bone, or brain metastases.

Very high serum markers.

Primary mediastinal nonseminoma.

Large number of lung metastases.

Even patients with widespread metastases at presentation, including those

with brain metastases, may still be curable and should be treated with this

intent.

Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the

procedure of choice in treating a malignant testicular mass. Evaluation of the

retroperitoneal lymph nodes usually by CT scanning is an important aspect of

treatment planning in adults with testicular cancer. An important aspect of the

diagnosis and follow-up of testicular cancer is the use of serum markers. Serum

markers include AFP, hCG (measurement of the beta subunit reduces luteinizing

hormone cross-reactivity), and lactate dehydrogenase. The serum markers may

detect a tumor that is too small to be detected on physical examination or x-rays.

Serum markers plus chest x-rays are important parts of the monthly checkups for

patients after definitive therapy of testicular cancer as well as periodic abdominal

computed tomographic (CT) scans for 2 to 3 years. The absence of markers does not

mean the absence of tumor. Patients typically receive follow-up monthly for the first

year and every other month for the second year after diagnosis and treatment.

While the majority of tumor recurrences appear within 2 years, late relapse has been

reported, and lifelong marker, radiologic, and physical examination is recommended.

Since the majority of testis cancer patients who receive chemotherapy are curable, it

is important to be aware of possible long-term effects of platinum-based treatment

such as cisplatin, bleomycin, and etoposide, some of which may be very serious

(e.g., infertility, secondary leukemias, bilateral hearing deficits, etc.). Bleomycin is

known for its pulmonary toxic effects may, but it is rarely fatal at the total

cumulative doses used and are reversible after the completion of chemotherapy.

In contrast to the excellent outcomes for men with good risk advanced testicular

tumors, up to 50% of men who have features of intermediate or poor risk disease

will require salvage therapy for relapsed disease following first-line chemotherapy.

Once relapse after cisplatin-containing therapy is diagnosed, the optimal treatment

for men depends upon the initial treatment and response to prior therapy, the

location and timing of the relapse, the stage of the tumor, the extent of the disease

and tumor histology. Most patients can still be cured. A single autologous stem cell

transplantation to treat testicular tumors in patients that do not achieve a complete

remission or in patients in second complete remission or in second relapse has

become standard of care. Planned tandem high-dose chemotherapy regimens with


autologous stem cell transplant followed by allogeneic stem cell donation of a

matched family member has also been accepted treatment despite the level of

evidence supporting its use rises to include multiple case series.

Ayash et al (2001) reported their results of double dose-intensive chemotherapy

with autologous stem cell support for relapsed and refractory testicular cancer and

reviewed the literature. They concluded that patients with relapsed/ refractory

testicular cancer benefit most from ABMT if they have platinum-sensitive disease in

first relapse. Patients, who do poorly despite ABMT have a mediastinal primary site,

true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly

elevated betaHCG at ABMT.

Multiple Myeloma Multiple myeloma is a hematological malignancy composed of an expanding clone of

plasma cells within the bone marrow. Multiple myeloma is a classic example of a

monoclonal proliferation of tumor cells: in 90% of cases the disease is characterized

by the plasma cell production of a monoclonal immunoglobulin, often referred to as a

M-component, which can be quantified in the serum or urine. The expansion of the

malignant clone of cells in the bone marrow with associated destruction of bone, and

the production of the M-component lead to the classic signs/symptoms of MM: lytic

bone lesions with painful fractures, hypercalcemia, anemia, amyloidosis, renal failure

as well as infections associated with immunodeficiency. Approximately 50% of

patients are older than 65 years of age at diagnosis.

Multiple myeloma is highly treatable but rarely curable. The disease is staged by

estimating the myeloma tumor cell mass on the basis of the amount of monoclonal

(or myeloma) protein (M protein) in the serum and/or urine, along with various

clinical parameters, such as the hemoglobin and serum calcium concentrations, the

number of lytic bone lesions, and the presence or absence of renal failure. The stage

of the disease at presentation is a strong determinant of survival, but it has little

influence on the choice of therapy since almost all patients, except for rare patients

with solitary bone tumors or extramedullary plasmacytomas, have generalized

disease. Treatment selection is influenced by the age and general health of the

patient, prior therapy, and the presence of complications of the disease.

Stages of Multiple Myeloma

Stage Description

I

All of the following:

Hemoglobin greater than 100 g/L (10 g/dL); and

Serum calcium less than 3 mM/L (12 mg/dL); and

Normal bone x-ray or solitary lesion; and

Low M-component production as evidenced by:

IgG level less than 50 g/l (5 g/dL); and

IgA less than 30 g/L (3 g/dL); and

Urine light chain (kappa or lambda) less than 4

g/24 hr; and

Estimated myeloma cell mass less than 0.6 trillion

cells/m2 (low burden).

Subclassification by impaired renal function worsens


prognosis regardless of stage:

Creatinine less than 2.0 mg/dL.

Creatinine greater than or equal to 2.0 mg/dL.

II

Fitting neither Stage I nor Stage III (Overall data not

as minimally abnormal as shown for Stage I and no

single value abnormal as defined for Stage III); and

Estimated myeloma cell mass 0.6 to 1.2 trillion cells/m2

(intermediate burden).

III

One or more of the following:

Hemoglobin less than 85 g/L (8.5 g/dL)

Serum calcium greater than 3 mM/L (12 mg/dL)

Advanced lytic bone lesions

High M-component production as shown by:

IgG greater than 70 g/L (7 g/dL)

IgA greater than 50 g/L (5 g/dL)

Urine light chain (kappa or lambda) greater than

12 g/24 hours

Estimated myeloma cell mass greater than 1.2 trillion

cells/m2 (high burden).

Systemic antineoplastic therapy is the initial approach to treatment for patients with

signs and symptoms of progressive disease. For the past two decades, the

combination of melphalan and prednisone has been the standard therapy for MM. For

patients who have proven to be resistant to this therapy, a combination of

vincristine, adriamycin with dexamethasone (VAD) has been implemented. The

literature indicates that multi-drug combinations have failed to substantially improve

the results originally obtained with standard melphalan and prednisone.

Approximately 40 to 50% respond initially (using 50% tumor reduction criteria),

although the incidence of true complete remission is rare, probably lower then 10%.

The median survival does not exceed 3 years. About 5% of patients, mainly those

presenting with low tumor mass and responding to initial therapy, survive 10 and 15

years, but eventually succumb to their disease.

High dose chemotherapy (HDC) followed by stem cell transplant (preferably

autologous) has been shown to be a treatment of choice for select patients with MM.

This is done in an attempt to obtain greater and more extended response rates by

permitting the use of chemotherapeutic agents at doses that exceed the myelo-

toxicity threshold; consequently, a greater tumor cell kill might be anticipated. Total

body irradiation (TBI) is an additional variable. A variety of regimens have been

developed for MM, which primarily involve the use of different alkylating agents.

Patients with the disease who are responsive to standard doses of chemotherapy,

and are either asymptomatic or have a good performance status and who do not

have any serious co-morbidities are considered optimal candidates for HDC.

It has been suggested that better results might be obtained with tandem (double or

sequential) autologous hematopoietic cell transplants. One such regimen consists of

melphalan for the first transplant and either the same dose or melphalan plus total

body irradiation for the second transplant, depending upon the response status prior

to the second transplant, which was usually performed within six months. In a

recent review on the treatment strategies for MM, Gisslinger and Kees (2003) stated,


“the use of tandem transplantation, developed to further escalate the conditioning

dose, has achieved additional improvement in survival”.

In a randomized study, Attal et al (2003) evaluated treatment of MM with HDC

followed by either one or two successive ASCT. A total of 399 previously untreated

patients under the age of 60 years were randomly assigned to receive a single, or

double transplant. A complete or a very good partial response was achieved by 42%

of patients in the single-transplant group and 50% of patients in the double-

transplant group (p = 0.10). The probability of surviving event-free for 7 years after

the diagnosis was 10% in the single-transplant group and 20% in the double-

transplant group (p = 0.03). The estimated overall 7-year survival rate was 21% in

the single-transplant group and 42% in the double-transplant group (p = 0.01).

Among patients who did not have a very good partial response within 3 months after

one transplantation, the probability of surviving 7 years was 11% in the single-

transplant group and 43% in the double-transplant group (p < 0.001). The authors

concluded that as compared with a single ASCT after HDC, double transplantation

improves overall survival among patients with MM, especially those who do not have

a very good partial response after undergoing one transplantation.

Stadtmauer et al (2003) conducted a randomized trial of 399 previously untreated

patients < 60 years of age from France found significantly improved seven-year

event-free survival (20 versus 10%) and overall survival (42 versus 21%) in

recipients of double versus single autologous transplant. Factors predicting for longer

survival in this study included low levels of beta-2-microglobulin and lactate

dehydrogenase at diagnosis, and younger age. The beneficial effect of the second

transplant on overall survival differed according to the response to the first

transplant. Patients who achieved a complete response (CR) or very good partial

response (VGPR) with the first transplant did not benefit significantly from the

second transplant. On the other hand, patients who did not have at least a VGPR to

the first transplant had a significant benefit from the second; seven year rates of

overall survival for this group were 11 versus 43% for those in the single or double

transplantation groups, respectively. The authors stated, as did the accompanying

editorial, that one reason the patients in the double transplant group might have

done better was that they received a higher overall dose of melphalan. There was

the suggestion that had the patients received 200 mg of melphalan for the first

transplant (without total body irradiation [TBI]), instead of the 140 mg/m2 dose with

TBI, they might not have needed the second transplant, putting these results into

some question. Results of other randomized trials are pending. However, as stated

earlier and based on the results discussed above, it is reasonable to consider a

second (tandem) HCT in patients failing to achieve CR or VGPR with the first

transplant.

An alternative to tandem transplant is to perform an initial autologous transplant

with one-half of the collected stem cells, and to perform a second autologous

transplant with the remaining cells after relapse. One early study suggests that this

strategy produces results equivalent to those reported with tandem transplantation.

However, results of a European registry retrospective analysis suggested that best

results were obtained when the second transplant was performed before relapse and

within 6 to 12 months of the first transplant. Since patients achieving CR or VGPR

with the first HCT do not appear to benefit from a tandem HCT approach, the second

transplant in this population can be reserved for relapsed disease.


Few patients are considered eligible for a second autologous stem cell transplant to

treat myeloma that has relapsed after a complete or partial remission that followed

an initial autotransplant. Thus, it is unlikely that prospective trials will ever be

conducted to rigorously compare outcomes of this strategy with alternatives.

Nevertheless, retrospective studies report durable complete or partial responses and

extended survival for patients treated this way, particularly when a long disease- or

progression-free interval followed the first transplant. Several peer reviewed

published case series report complete response rates after allogeneic transplant in

patients with myeloma range from 22% to 67%. A number of observations suggest

that graft-vs-myeloma effects occur following allogeneic transplantation, including

the identification of myeloma-specific cytotoxic T cells in transplant recipients and

clinical responses to donor lymphocyte infusions.

A study published by Maloney (2003) included 54 patients with previously treated

myeloma (52% refractory or relapsed disease) given an initial autologous stem cell

transplant conditioned with 200 mg/m2 melphalan. Of these, 52 received a

subsequent mini-allogeneic stem cell transplant. Investigators reported 78% overall

survival (OS) at a median 552 days after allografting. Treatment achieved a

complete remission (CR) in 57% and an overall response rate of 83%. Acute graft-

versus host-disease (GVHD) developed in 38% of patients, and chronic GVHD

requiring therapy in 46%. Twelve patients died: 1 from viral infection after the initial

autotransplant, 2 from myeloma progression (3 and 23 months post-mini-

allotransplant), 7 from GVHD, and 1 each from lung cancer and encephalopathy.

Multiple myeloma also includes indolent myeloma, smoldering myeloma and MGUS.

With conventional-dose chemotherapy, patients with MM have a median survival of

about 3 years, while the disease course of indolent and smoldering myeloma and

MGUS is more uncertain. Therefore, the distinction between these entities is

important because HDC is clearly indicated only in cases of symptomatic MM.

Review History March 2007 Medical Advisory Council initial approval

December 2010 Update. Added Medicare table with link to NCD. No revisions.

March 2012 Update - no revisions. Code updates.

March 2013 Update – no revisions. Code updates.

May 2013 Added that tandem transplant can be considered as an option for multiple

myeloma patients who do not achieve at least a very good partial

response (VGPR) after the first autologous SCT. (NCCN Multiple Myeloma

2013)

May 2014 Update – Clarified policy statement noting that tandem SCT can be done

with autologous stem cells as recommended by NCCN guidelines.

May 2015 Update – no revisions

May 2016 Update – no revisions. Codes updated.

June 2017 Update- no revisions

This policy is based on the following evidence-based guidelines: 1. Imrie K; Esmail R; Meyer RM. The role of high-dose chemotherapy and stem-cell

transplantation in patients with multiple myeloma: a practice guideline of the

Cancer Care Ontario Practice Guidelines Initiative. Ann Intern Med. 2002;

136(8):619-629.

2. American Society for Blood and Bone Marrow Transplantation. Policy

Statements, Guidelines and Reviews.


3. Myeloma Management Guidelines. A Consensus Report From The Scientific

Advisors Of The International Myeloma Foundation. Available at:

http://www.myeloma.org/pdfs/MyelomaManagementGuidelines.pdf

4. Anderson KC, Alsina M, Bensinger W, et al; National Comprehensive Cancer

Network (NCCN). Multiple myeloma. Clinical practice guidelines in oncology. J

Natl Compr Canc Netw. 2009; 7 (9): 908-942.

5. National Cancer Comprehensive Network (NCCN) Clinical Practical Guidelines in

Oncology. Testicular Cancer. V.2.2010. Update Version 1.2012. Update 1.2014.

Update 1.2015. Updated Version 2.2016.

6. National Cancer Comprehensive Network (NCCN) Clinical Practical Guidelines in

Oncology. Multiple Myeloma, Version 1.2011. Update Version 1.2013. Update

version 2.2014. Update Version 4.2015. Update Version 3.2016. 7. Imrie K, Rumble RB, Crump M, Advisory Panel on Bone Marrow and Stem Cell

Transplantation, Hematology Disease Site Group. Stem cell transplantation in

adults: recommendations. Toronto (ON): Cancer Care Ontario Program in

Evidence-based Care; 2009 Jan 30. 78 p. Available at:

https://www.cancercare.on.ca/common/pages/UserFile.aspx?serverId=6&path=

/File%20Database/CCO%20Files/PEBC/pebc_stemcell.pdf

References – Update May 2016 1. Palumbo A, Cavallo F, F, et al. Autologous Transplantation and Maintenance Therapy in

Multiple Myeloma. NEJM. 2014;371:895-905.

References – Update May 2015 1. Byrne M, Salmasinia D, Leather H, et al. Tandem Autologous Stem Cell Transplantation

for Multiple Myeloma Patients Based on Response to Their First Transplant-A

Prospective Phase II Study. Clin Med Insights Oncol. 2014 Sep 3;8:101-5

2. Iacobelli S, de Wreede LC, Schönland S, et al. Impact of CR before and after allogeneic

and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000

prospective trial. Bone Marrow Transplant. 2015 Apr;50(4):505-10.

3. Tamura H. Single vs double stem cell transplantation for the treatment of multiple

myeloma. Nihon Rinsho. 2015 Jan;73(1):85-9.

References – Update May 2014 1. Agarwala AK, Perkins SM, Abonour R, et al. Salvage chemotherapy with high-dose

carboplatin and etoposide with peripheral blood stem cell transplant in patients with

relapsed pure seminoma. Am J Clin Oncol. 2011 Jun;34(3):286-8.

2. Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced

intensity allogeneic transplantation in the upfront management of multiple myeloma:

meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013

Apr;48(4):562-7.

3. Brito M, Sanchez P, Velho S, et al. High dose chemotherapy with autologous stem-cell

support in germ cell tumors: The Instituto Português de Oncologia de Lisboa Francisco

Gentil Series. Acta Med Port. 2011 Jul-Aug;24(4):533-44.

4. Connolly RM, McCaffrey JA. High-dose chemotherapy plus stem cell transplantation in

advanced germ cell cancer: a review. Eur Urol. 2009 Jul;56(1):57-64.

5. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell

rescue for metastatic germ-cell tumors. N Engl J Med. 2007 Jul 26;357(4):340-8.

6. Gahrton G, Iacobelli S, Björkstrand B, et al. Autologous/reduced-intensity allogeneic

stem cell transplantation vs autologous transplantation in multiple myeloma: long-term

results of the EBMT-NMAM2000 study. Blood. 2013 Jun 20;121(25):5055-63.

http://www.myeloma.org/pdfs/MyelomaManagementGuidelines.pdf

https://www.cancercare.on.ca/common/pages/UserFile.aspx?serverId=6&path=/File%20Database/CCO%20Files/PEBC/pebc_stemcell.pdf

https://www.cancercare.on.ca/common/pages/UserFile.aspx?serverId=6&path=/File%20Database/CCO%20Files/PEBC/pebc_stemcell.pdf


7. Gohji K, Hara I, Yamada Y, et al. Clinical results of super high-dose chemotherapy with

peripheral blood stem cell transplantation for patients with advanced germ cell tumor.

Hinyokika Kiyo. 1999 Nov;45(11):799-804.

8. Hara I, Yamada Y, Kumano M, et al. High dose chemotherapy including paclitaxel (T-

ICE) combined with peripheral blood stem cell transplantation for male germ cell tumor.

Preliminary report. Int J Urol. 2005 Dec;12(12):1074-8.

9. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al. Comparative efficacy of tandem

autologous versus autologous followed by allogeneic hematopoietic cell transplantation

in patients with newly diagnosed multiple myeloma: a systematic review and meta-

analysis of randomized controlled trials. J Hematol Oncol. 2013 Jan 4;6:2.

10. Koychev D, Oechsle K, Bokemeyer C, Honecker F. Treatment of patients with relapsed

and/or cisplatin-refractory metastatic germ cell tumours: an update. Int J Androl. 2011

Aug;34(4 Pt 2):e266-73.

11. Kozelj M, Zver S, Zadnik V. Long term follow-up report of cardiac toxicity in patients

with multiple myeloma treated with tandem autologous hematopoietic stem cell

transplantation. Radiol Oncol. 2013 May 21;47(2):161-5.

12. Ladicka M, Ballova V, Drgona L, et al. Tandem autologous stem cell transplantation in

multiple myeloma after high-dose chemotherapy with two separate collections: single

institution experience. Neoplasma. 2012;59(5):551-8.

13. Lazarus HM, Stiff PJ, Carreras J, et al. Utility of single versus tandem autotransplants

for advanced testes/germ cell cancer: a center for international blood and marrow

transplant research (CIBMTR) analysis. Biol Blood Marrow Transplant. 2007

Jul;13(7):778-89.

14. Marjanović S, Cerović S, Brajusković G. Use of high-dosage chemotherapy with

autologous hematopoietic stem cell transplantation as a first-line therapy for the

patients with poor-prognosis testicular tumors. Vojnosanit Pregl. 2005 Mar;62(3):213-

8.

15. Michallet M, Sobh M, El-Cheikh J, et al. Evolving strategies with immunomodulating

drugs and tandem autologous/allogeneic hematopoietic stem cell transplantation in first

line high risk multiple myeloma patients. Exp Hematol. 2013 Dec;41(12):1008-15.

16. Miki T, Mizutani Y, Akaza H, et al. Long-term results of first-line sequential high-dose

carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell

support for patients with advanced testicular germ cell tumor. Int J Urol. 2007

Jan;14(1):54-9.

17. Miyazaki J, Miyanaga N, Kawai K, et al. High-dose chemotherapy with peripheral blood

stem cell transplantation for advanced testicular cancer. Int J Urol. 2000 Jul;7(7):258-

62.

18. Naumann-Winter F, Greb A, Borchmann P, et al. First-line tandem high-dose

chemotherapy and autologous stem cell transplantation versus single high-dose

chemotherapy and autologous stem cell transplantation in multiple myeloma, a

systematic review of controlled studies. Cochrane Database Syst Rev. 2012 Oct

17;10:CD004626

19. Rosiñol L, Kumar S, Moreau P, Cavo M. Initial treatment of transplant-eligible patients

in multiple myeloma. Expert Rev Hematol. 2014 Feb;7(1):43-53.

References – Update May 2013 1. Bergantim R, Trigo F, Guimarães JE. Impact of tandem autologous stem cell

transplantation and response to transplant in the outcome of multiple myeloma. B Exp

Hematol Oncol. 2012; 1: 35. 2012 November 26. doi: 10.1186/2162-3619-1-

35PMCID: PMC3547750.

2. Delgado JC. Diagnosis of Monoclonal Gammopathies. ARUP Laboratories. Available at:

http://www.arup.utah.edu/media/gammopathies/2011%20Jan%20-

%20Monoclonal%20Gammopathies.pdf

http://www.arup.utah.edu/media/gammopathies/2011%20Jan%20-%20Monoclonal%20Gammopathies.pdf

http://www.arup.utah.edu/media/gammopathies/2011%20Jan%20-%20Monoclonal%20Gammopathies.pdf


3. Lakshminarayanan R, Li Y, Janatpour K, et al. Detection by Immunofixation of M

Proteins in Hypogammaglobulinemic Patients With Normal Serum Protein

Electrophoresis Results. Immunopathology/ M Proteins Hypogammaglobulinemic

Patients. American Society for Clinical Pathology. 2007;127:746-751.

4. O’Connell TX, Horita TJ, Kasravi B. Understanding and Interpreting Serum Protein

Electrophoresis. m Fam Physician. 2005 Jan 1;71(1):105-112.

References – Update March 2013 1. Bjorkstrand B, Iacobelli S, Hegenbart U, et al. Tandem autologous/reduced-intensity

conditioning allogeneic stem-cell transplantation versus autologous transplantation in

myeloma: Long-term follow-up. J Clin Oncol. 2011;29 (22):3016-3022.

2. Canellos GP, Mauch PM. Hematopoietic cell transplantation in classical Hodgkin

lymphoma. UpToDate. April 19, 2012.

3. Harmon DC, Gebhardt MC. Treatment of the Ewing sarcoma family of tumors.

UpToDate. December 11, 2012.

4. Kieran MW. Ependymoma. UpToDate February 12, 2013.

5. Rajkumar SV. Clinical presentation, laboratory manifestations, and diagnosis of

immunoglobulin light chain (AL) amyloidosis (primary amyloidosis). UpToDate.

November 27, 2012.

6. Rajkumar SV. Treatment and prognosis of Waldenström macroglobulinemia. UpToDate.

February 22, 2013.

7. Sureda A, Canals C, Arranz R, et al. Allogeneic stem cell transplantation after reduced

intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma.

Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de

Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of

the European Group for Blood and Marrow Transplantation. Haematologica. 2012

Feb;97(2):310-7. Epub 2011 Oct 11.

References – Update March 2012 1. Bashir Q, Khan H, Orlowski RZ, et al. Predictors of prolonged survival after allogeneic

hematopoietic stem cell transplantation for multiple myeloma. Am J Hematol. 2011 Dec

17. doi: 10.1002/ajh.22273.

2. Khalafallah A, McDonnell K, Dawar HU, et al. Quality of life assessment in multiple

myeloma patients undergoing dose-reduced tandem autologous stem cell

transplantation. Mediterr J Hematol Infect Dis. 2011;3(1):e2011057

3. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell

transplantation followed by allogeneic or autologous haemopoietic stem-cell

transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological

assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203

4. Matsui W, Borrello I, Mitsiades C. Autologous stem cell transplantation and multiple

myeloma cancer stem cells. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S27-

32.

5. Rigacci L, Puccini B, Dodero A, et al. Allogeneic hematopoietic stem cell transplantation

in patients with diffuse large B cell lymphoma relapsed after autologous stem cell

transplantation: A GITMO study. Ann Hematol. 2012 Jan 14

References Update - December 2010 1. CMS. Centers for Medicare & Medicaid. NCD for Stem Cell Transplantation (110.8.1).

Implementation Date 11/10/2010.


2. Barlogie B, Attal M, Crowley J, et al. Long term follow up on auto-transplantation trials

for multiple myeloma; update of protocols. Journal of Clinical Oncology; 2010 28: 1209-

1214.

3. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al. Tandem versus single autologous

hematopoietic cell transplantation for the treatment of multiple myeloma: A systematic

review and meta-analysis. J Natl Cancer Inst. 2009;101 (2):100-106.

4. Agarwal R, Dvorak CC, Stockerl-Goldstein KE, et al. High-dose chemotherapy followed

by stem cell rescue for high-risk germ cell tumors: the Stanford experience. Bone

Marrow Transplant. 2009 Apr;43(7):547-52.

5. Ryan CJ, Small EJ, Torti FM. Abeloff: Abeloff's Clinical Oncology, 4th ed. Chapter 90

Testicular Cancer. 2008.

6. Lazarus HM, Stiff PJ, Carreras J, et al. Utility of single versus tandem autotransplants

for advanced testes/germ cell cancer: a center for international blood and marrow

transplant research (CIBMTR) analysis. Biol Blood Marrow Transplant. 2007 Jul;13

(7):778-89.

7. Lorch A, Kollmannsberger C, Hartmann JT, et al. Single versus sequential high-dose

chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective

randomized multicenter trial of the German Testicular Cancer Study Group. J Clin Oncol.

2007 Jul 1;25 (19):2778-84.

References Initial 1. Elice, F, Raimondi, R, Tosetto, A, et al. Prolonged overall survival with second

on-demand autologous transplant in multiple myeloma. Am J Hematol 2006;

81:426.

2. Kopp HG, Kuczyk M, Classen J, et al. Advances in the treatment of testicular

cancer. Drugs. 2006;66(5):641-59.

3. Barlogie, B, Tricot, G, Anaissie, E, et al. Thalidomide and hematopoietic-cell

transplantation for multiple myeloma. N Engl J Med 2006; 354:1021.

4. Barlogie, B, Tricot, G, Rasmussen, E, et al. Total therapy 2 without thalidomide

in comparison with total therapy 1: role of intensified induction and

posttransplantation consolidation therapies. Blood 2006; 107:2633.

5. Margolin KA, Doroshow JH, Frankel P, et al. Paclitaxel-based high dose

chemotherapy with autologous stem cell rescue for germ cell cancer. Biol Blood

Marrow Transplant. 2005 Nov;11(11):903-11.

6. Morris, C, Iacobelli, S, Brand, R, et al. Benefit and timing of second

transplantations in multiple myeloma: clinical findings and methodological

limitations in a European group for blood and marrow transplantation registry

study. J Clin Oncol 2004; 22:1674.

7. Lahuerta, JJ, Grande, C, Martinez-Lopez, J, De La, Serna J. Tandem transplants

with different high-dose regimens improve the complete remission rates in

multiple myeloma. Results of a Grupo Espanol de Sindromes

Linfoproliferativos/Trasplante Autologo de Medula Osea phase II trial. Br J

Haematol 2003; 120:296.

8. Fassas, AB, Barlogie, B, Ward, S, et al. Survival after relapse following tandem

autotransplants in multiple myeloma patients: The University of Arkansas total

therapy I experience. Br J Haematol 2003; 123:484.

9. Barlogie, B, Tricot, GJ, van Rhee, F, et al. Long-term outcome results of the first

tandem autotransplant trial for multiple myeloma. Br J Haematol 2006;

135:158.

10. Jacobson, J, Barlogie, B, Shaughnessy, J, Drach, J. MDS-type abnormalities

within myeloma signature karyotype (MM-MDS): only 13% 1-year survival

despite tandem transplants. Br J Haematol 2003; 122:430.


11. Attal, M, Harousseau JL, Facon T, et al. Single versus double autologous stem-

cell transplantation for multiple myeloma. NEJM. 2003;349:2495-2502.

12. de Giorgi U, Papiani G, Severini G, et al. High-dose chemotherapy in adult

patients with germ cell tumors. Cancer Control. 2003;10(1):48-56.

13. Tricot, G, Spencer, T, Sawyer, J, et al. Predicting long-term (5 years) event-free

survival in multiple myeloma patients following planned tandem autotransplants.

Br J Haematol 2002; 116:211.

14. Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci U S A. 2002

Apr 2;99(7):4592-5.

15. Anagnostopoulos A, Giralt S. Critical review on non-myeloablative stem cell

transplantation (NST). Crit Rev Oncol Hematol. 2002;44(2):175-190.

16. Barbui AM, Galli M, Dotti G, et al. Negative selection of peripheral blood stem

cells to support a tandem autologous transplantation programme in multiple

myeloma. Br J Haematol. 2002; 116(1):202-210.

17. Child JA, Morgan GJ, Gilson D, et al. High-dose chemotherapy with

hematopoietic stem-cell rescue for multiple myeloma. NEJM. 2003;

348(19):1875-1883.

18. Kröger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation

followed by a dose-reduced allograft induces high complete remission rate in

multiple myeloma. Blood. 2002; 100(3):755-760.

19. Dalton WS, Bergsagel PL, Kuehl WM, et al. Multiple myeloma. Hematology (Am

Soc Hematol Educ Program). 2001;157-177.

20. Ayash LJ, Clarke M, Silver SM, et al. Double dose-intensive chemotherapy with

autologous stem cell support for relapsed and refractory testicular cancer: the

University of Michigan experience and literature review. Bone Marrow

Transplant. 2001 May;27(9):939-47.

21. Oliver RT. Testicular cancer. Curr Opin Oncol. 2001 May;13(3):191-8.

22. Sirohi, B, Powles, R, Singhal, S, et al. High-dose melphalan and second

autografts for myeloma relapsing after one autograft: Results equivalent to

tandem autotransplantation. Blood 2001; 98:402a.

23. Attal M, Harousseau JL. Randomized trial experience of the Intergroupe

Franchophone du Myelome Semin Hematol. 2001;38:226-30.

24. Badros A, Barlogie B, Morris C, et al. High response rate in refractory and poor-

risk multiple myeloma after allotransplantation using a nonmyeloablative

conditioning regimen and donor leukocyte infusions. Blood. 2001;97(9):2574-

2579.

25. Bhatia S, Abonour R, Porcu P, et al. High-dose chemotherapy as initial salvage

chemotherapy in patients with relapsed testicular cancer. JCO.

2000;18(19):3346-3351.

26. Sobecks RM, Vogelzang NJ. High dose chemotherapy with autologous stem-cell

support for germ cell tumors. A critical review. Semin Oncol. 1999;26:106-18.

27. Barlogie, B, Jagannath, S, Desikan, KR, et al. Total therapy with tandem

transplants for newly diagnosed multiple myeloma. Blood 1999; 93:55.

28. Murty VV, Chaganti RS. A genetic perspective of male germ cell tumors. Semin

Oncol. 1998 Apr;25(2):133-44.

29. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous

peripheral blood stem cell transplantation in multiple myeloma: up-front or

rescue treatment? Results of a multicenter sequential randomized clinical trial.

Blood. 1998; 92(9):3131-3136.

30. Schmoll KJ, Beyer J. Prognostic factors in metastatic germ cell tumors. Seminars

in Oncology. 1998;25(2):174-186.


31. Broun ER, Nichols CR, Gize G, et al. Tandem high dose chemotherapy with

autologous bone marrow transplantation for initial relapse of testicular germ cell

cancer. Cancer. 1997 Apr 15;79(8):1605-10.

32. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous

transplantation over standard therapy for previously untreated multiple

myeloma. Blood. 1997; 89(3):789-793.

33. Bataille R, Harousseau JL. Multiple myeloma. NEJM. 1997;336(23):1657-1664.

34. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of

autologous bone marrow transplantation and chemotherapy in multiple

myeloma. NEJM. 1996;335(2):91-97.

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